The general term “pain” is defined here to represent all categories of physical pain. This includes traumatic pain resulting from injury, surgery or inflammation. It also includes pain associated with diseases such as cancer, AIDS, arthritis, and herpes. Pain associated with neuropathy such as diabetic neuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, fibromyalgia, vulvodynia, prostadynia, pelvic pain, gout, and other forms of neuralgia, such as neuropathic and idiopathic pain syndromes are also included. Specific organ- or site-localized pain, such as headache, ocular and corneal pain, bone pain, urogenital pain, heart pain, skin/burn pain, lung pain, visceral (kidney, gall bladder, etc.) pain, joint pain, dental pain and muscle pain are further included in this invention. The general term “pain” also covers pain symptoms of varying severity, i.e. mild, moderate and severe pain, as well as those of acute and chronic pain.
Traumatic or nociceptive pain differs from neuropathic pain in that an external stimulus causes a normal sensory response to an insult or illness in the case of traumatic pain, whereas neuropathic pain results from injury to a portion of the nervous system and is typically not responsive to narcotic analgesics. Neuropathic pain often involves neural hypersensitivity and can persist without any overt external stimulus. (Goodman & Gilman's “The Pharmacologic Basis of Therapeutics”, 1996, p. 529, McGraw-Hill).
The therapeutic objective of most pain therapy is to alleviate the symptoms of pain regardless of the cause. Current pain-control therapies include the use of opioid narcotic analgesics such as morphine and fentanyl, nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen and cyclooxygenase inhibitors, or ion channel blockers such as lidocaine and novocaine. These therapies all have limitations, however. Opioids can cause tolerance, dependence, constipation, respiratory depression and sedation. NSAIDS have gastrointestinal side effects, can increase bleeding time, and are not effective in the treatment of severe pain. In the case of non-selective sodium channel blockers, central nervous system (CNS) side effects, cardiovascular side effects and corneal damage have been reported after use. Given the above limitations to currently known pain-control therapies, a need still exists for better pain-treatment methods.
Purine derivatives, acting via extracellular nucleotide receptors, have a variety of physiological and pathological roles in living tissues and cell types (Burnstock, Drug Dev. Res. 28:195-206 (1993)). Extracellular nucleotide receptors have been studied in a number of neurons from afferent and efferent nerve fibers including sensory, sympathetic, parasympathetic, mesenteric, and central neurons (Zhong, et al. Br. J. Pharmacol. 125:771-781 (1998)), and purines, such as ATP, function as excitatory neurotransmitters. These compounds are known to activate P2X receptors located on primary afferent nerve fibers and tissues of the spinal cord dorsal horn (Holton and Holton, J. Physiol. (Lond.) 126:124-140 (1954)). Neurons that process nociceptive information are also found in the spinal cord dorsal horn (Maciewicz, R. and Martin, J. B. in Harrison's Principles of Internal Medicine, 12th Edition, McGraw-Hill, Inc., New York, Jean D. Wilson, et al., editors, 1991, P.93).
Nucleotide receptors, in particular, P2X receptors, are known to form homomultimers or heteromultimers in vitro. Two of the receptors/subunits from the P2X family, P2X2 and P2X3, can form functional ATP-gated channels when expressed alone or when co-expressed in a heteromultimer form (P2X2/3). These heteromultimers produce ion currents which are similar to currents seen in native sensory channels (Lewis, et. al, Nature 377:432-435 (1995)). Furthermore, nociception has been documented to occur via stimulation of these P2X receptors (in particular within the previously described P2X2, P2X3 and P2X2/3 receptor types), and activation of these P2X receptors with agonists such as ATP or benzoylbenzoyl-ATP is associated with hyperalgesic action (Chizh and Illes, Pharmacol. Rev. 53:553-568 (2000); Jarvis and Kowaluk, Drug Development Res. 52:220-231 (2001)). A contrasting example of the causal relationship between antagonism of these P2X receptors and antinociception is provided by the ATP-ketal derivative, TNP-ATP, which has been shown to produce antinociceptive effects in rats (Jarvis and Kowaluk, 2001). Substances previously shown to antagonize these P2X receptors (such as TNP-ATP), however, are generally known to have thermal instability and/or receptor selectivity problems; hence they are poor candidates for pharmaceutical development. The need still exists for new pain treatment methods based on materials with good receptor selectivity, chemical stability and low incidences of side effects.
As described above, agents commonly used to treat pain may cause adverse side effects, and thus there is a continuing need for new agents that are both safe and effective in treating pain.